Early Improvements With Atogepant for the Preventive Treatment of Migraine
Results From 3 Randomized Phase 3 Trials
Abstract
Background and Objectives
Three phase 3 trials demonstrated the efficacy and safety of atogepant in episodic migraine (EM) and chronic migraine (CM) across 12-week treatment periods. This analysis evaluates improvements in efficacy and functional outcomes in the first 4 weeks of treatment with the oral calcitonin gene-related peptide receptor antagonist, atogepant, for the preventive treatment of migraine.
Methods
ADVANCE, ELEVATE, and PROGRESS were phase 3, multicenter, randomized, double-blind, placebo-controlled 12-week trials. ADVANCE and ELEVATE included participants aged 18–80 years with >1 year history of EM and 4–14 monthly migraine days (MMDs). ELEVATE required previous treatment failures to 2–4 classes of oral preventives. PROGRESS included participants aged 18–80 years with >1 year history of CM, ≥15 monthly headache days, and ≥8 MMDs. This analysis reports the atogepant 60 mg once daily (QD) and placebo treatment arms. Outcomes included efficacy endpoints (reporting a migraine day on day 1, change from baseline in weekly migraine days [WMDs] at weeks 1–4, and in MMDs in the first 4 weeks) and functional endpoints evaluated by the Activity Impairment in Migraine-Diary (AIM-D) at weeks 1–4 and the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) at weeks 1–2 and 4.
Results
The modified intent-to-treat population included the ADVANCE (atogepant, n = 222; placebo, n = 214), ELEVATE (atogepant, n = 151; placebo, n = 154), and PROGRESS (atogepant, n = 256; placebo, n = 246) studies. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1. The odds ratio compared with placebo was 0.39 (95% CI 0.23–0.67; p = 0.0006) in ADVANCE, 0.53 (95% CI 0.29–0.94, p = 0.031) in ELEVATE, and 0.63 (95% CI 0.43–0.93, p = 0.021) in PROGRESS. Atogepant treatment reduced WMDs at weeks 1–4 and MMDs in the first 4 weeks, and improved AIM-D and EQ-5D-5L at all assessed timepoints for weeks 1–4 compared with placebo.
Discussions
Atogepant 60 mg QD demonstrated superiority to placebo in efficacy and functional measures in the first 4 weeks of treatment across 3 preventive studies, 2 in EM and 1 in CM.
Trial Registration
ClinicalTrials.gov NCT03777059; NCT04740827; NCT03855137. Submitted: 12/13/2018; 02/02/2021; 02/25/2019. First patient enrolled: 12/14/2018; 03/05/2021; 03/11/2019 clinicaltrials.gov/ct2/show/NCT03777059. clinicaltrials.gov/ct2/show/NCT04740827 clinicaltrials.gov/ct2/show/NCT03855137.
Classification of Evidence
This study provides Class II evidence that atogepant 60 mg QD reduces migraine frequency and improves functional outcomes within 4 weeks of initiation in patients with EM and patients with CM.
Introduction
Migraine affects an estimated 1.1 billion individuals worldwide and is the second leading cause of disability in the general population, and the leading cause of disability in young, adult women.1-3 In addition, migraine causes more years lived with disability than all other neurologic diseases combined.2 Migraine substantially affects daily life during and between attacks, with patients reporting negative effects on relationships, parenting, career, and finances, all leading to an increase in daily stress and a lower quality of life.4-6 Owing to the high disability in the migraine population, treatments for migraine should have both a high efficacy and a rapid onset of action.7-9
Current conventional oral preventive treatments require dose titration and may take weeks to months to demonstrate maximum efficacy.10,11 In addition, individuals may experience suboptimal efficacy, safety, or tolerability issues, causing premature treatment discontinuation and cycling through multiple classes of conventional oral preventive treatments.12-15 The American Headache Society treatment guidelines state that a preventive migraine treatment should reduce the frequency and severity of attacks and also improve function and quality of life and reduce disability.13 Rapid onset of action may lead to earlier improvements in daily functioning, work productivity, and disability, reducing the overall effect of migraine on patient lives.
A rapid onset of action has been demonstrated from calcitonin gene–related peptide (CGRP) targeted monoclonal antibodies (mAbs).16-24 Current evidence suggests that oral CGRP receptor antagonists, or gepants, may be differentiated from conventional oral preventive treatments regarding speed of onset. Gepants do not require dose titration and have benefits as acute treatments. In prevention trials, atogepant and rimegepant have demonstrated efficacy over the first 4 weeks of treatment.13,25,26 In addition, preliminary analyses with atogepant for the preventive treatment of chronic migraine (CM) have demonstrated efficacy at day 1, and this report will expand on those analyses.27
Atogepant is an oral CGRP receptor antagonist approved for the preventive treatment of migraine in adults.28 The ADVANCE trial in episodic migraine (EM) and the PROGRESS trial in CM demonstrated the efficacy of atogepant compared with placebo on the primary endpoint of change from baseline in monthly migraine days (MMDs) over 12 weeks.29,30 The ELEVATE trial demonstrated the efficacy of atogepant compared with placebo on the primary endpoint of change from baseline in MMDs over 12 weeks in participants with EM who had previously been failed by 2–4 classes of conventional oral migraine preventive treatments.31 Here, we extend these previous analyses by using data from 3 large trials (ADVANCE, ELEVATE, and PROGRESS) to address the primary research question of evaluating the early outcomes of atogepant 60 mg once daily (QD) (efficacy on day 1, and efficacy and functional outcomes weekly for the first 4 weeks, and across the first 4-week period).
Methods
Study Design
Full methodological details for ADVANCE (NCT03777059, conducted within the United States), ELEVATE (NCT04740827, conducted in North America and Europe), and PROGRESS (NCT03855137, conducted in North America, Europe, and East Asia), including study design, dates, size, randomization and blinding, and inclusion and exclusion criteria, have been previously published.29-31
In ADVANCE, participants were randomized 1:1:1:1 to receive atogepant 10 mg QD, 30 mg QD, 60 mg QD, or placebo. In PROGRESS, participants were randomized 1:1:1 to receive atogepant 30 mg twice daily (BID), 60 mg QD, or placebo. In ELEVATE, participants were randomized 1:1 to receive atogepant 60 mg QD or placebo (eFigure 1). All analyses reported here include the approved atogepant dose of 60 mg QD, the only dose common among all 3 trials.
Participants
ADVANCE and ELEVATE included adults 18–80 years old with ≥1-year history of EM with or without aura, defined using the International Classification of Headache Disorders, 3rd edition (ICHD-3).29,31,32 Participants had 4–14 migraine days per month (based on patient history) in the 3 months before visit 1 and in the 4-week screening/baseline period per the electronic diary (eDiary), with a migraine onset at less than 50 years of age. PROGRESS included adults 18–80 years with ≥1-year history of CM, defined using ICHD-3 criteria, with migraine onset at less than 50 years. Participants had ≥15 headache days per month (based on patient history) in ≥3 months before the baseline/screening visit, and ≥15 headache days, including ≥8 migraine days during the 4-week baseline period based on eDiary. In ADVANCE and PROGRESS, participants could have a previous inadequate response to ≤4 conventional oral migraine preventive treatments. ELEVATE required participants who had previously been failed by 2–4 classes of conventional oral migraine preventive treatments, based on study definitions for lack of efficacy, tolerability, or both. PROGRESS allowed enrollment of participants with acute medication overuse at baseline, whereas ADVANCE and ELEVATE did not. Additional key inclusion and exclusion criteria are in the eMethods.
Outcomes
The primary endpoint in all 3 trials was change from baseline in mean MMDs across the 12-week treatment period.29-31 The efficacy endpoints and the functional endpoints evaluated using the European Quality-of-Life-5 Dimensions-5 Level (EQ-5D-5L) were prespecified additional analyses. The functional endpoints evaluated using the Activity Impairment in Migraine-Diary (AIM-D) were post hoc analyses.
Reporting a Migraine Day on Day 1
The proportion of participants with a migraine day were reported as the number and percentage of participants meeting migraine criteria on day 1 postdose. Baseline values were defined as the average of MMDs during the 28-day baseline period divided by 28 and multiplied by 100.
Change From Baseline in Weekly Migraine Days (WMDs) at Weeks 1–4
WMDs were calculated using the average number of migraine days during each of the 7-day periods. Baseline values were defined as MMDs over 4 weeks divided by 4 to compute the 1-week average.
Change From Baseline in Mean MMDs During the First 4 Weeks of Treatment
MMDs were calculated using the average number of migraine days during weeks 1–4. Baseline values were defined as the number of migraine days during the 28 days before randomization.
Change From Baseline in AIM-D Domains at Weeks 1–4
AIM-D has been previously psychometrically validated in a 13-week prospective observational study, as well as using phase 3 clinical trial data from ADVANCE and PROGRESS; detailed methods have been previously published.33,34 AIM-D is an 11-item daily diary measure assessing functioning and activity impairment, scored in 2 domains. Participants completed the eDiary once daily throughout the trial. Performance of daily activities (PDA) is a 7-item domain where participants rate the level of difficulty experienced in the past 24 hours with performance of daily activities. Physical impairment (PI) is a 4-item domain where participants rate their level of PI in the past 24 hours. AIM-D endpoints included change from baseline in PDA and PI domain scores at weeks 1, 2, 3, and 4; proportion of participants achieving meaningful within-patient change (MWPC) estimates in the PDA domain score at weeks 1, 2, 3, and 4 (≥9 point [EM] or ≥13.1 point [CM] improvement from baseline); and proportion of participants achieving MWPC estimates in the PI domain score at weeks 1, 2, 3, and 4 (≥6 point [EM] or ≥10 point [CM] improvement from baseline).35,36
Change From Baseline EQ-5D-5L Scores at Weeks 1–2 and 4
EQ-5D-5L measures health status and consists of 2 components, the Descriptive System Index and Visual Analogue Scale (VAS). The Descriptive System Index score assesses current health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Participants provided their response to their health state for each statement, and the scoring range was from “dead” (0) to “full health” (1). The VAS assessed the participant's self-rated health on a scale from “worst imaginable health” (0) to “best imaginable health” (100). EQ-5D-5L was collected in an eDiary for the last 7 days in the screening/baseline period, randomization until visit 3 (14 consecutive days from randomization), visit 4 (days 25–31), visit 5 (days 39–45), visit 6 (days 53–59), and visit 7 (days 77–83). At visit 8, the EQ-5D-5L was administered on an eTablet. EQ-5D-5L endpoints included change from baseline in the Descriptive System Index score and VAS score at weeks 1–2 and 4. EQ-5D-5L was evaluated in all 3 trials; however, only ELEVATE and PROGRESS evaluated EQ-5D-5L at weeks 1–2 and 4; thus, ADVANCE is not included in the EQ-5D-5L analysis.
Adverse Events
Adverse events (AEs) were collected from the time of consent through the last visit, including the baseline/screening period, the double-blind treatment period, and the follow-up period for all trials. Safety parameters included the incidence of AEs, serious AEs, AEs leading to discontinuation, and clinical laboratory evaluations; vital signs; electrocardiograms; and the Columbia-Suicide Severity Rating Scale. Treatment-emergent AEs (TEAEs) were defined as AEs with a recorded onset date on or after the date of the first dose of double-blind study treatment and within 30 days after the last dose of the study treatment. TEAEs reported here were those recorded within the first 4 weeks of study treatment.
Statistical Analyses
Determination of sample sizes were previously described.29-31 All analyses were performed using the modified intent-to-treat (mITT) population, consisting of all randomized participants who received ≥1 dose of study intervention, had an evaluable baseline period of eDiary data, and had ≥1 evaluable postbaseline 4-week period of eDiary data during the double-blind treatment period. The safety population consisted of all participants who received ≥1 dose of study intervention analyzed according to actual treatment received. Baseline MMDs were calculated during the 28-day baseline period with ≥20 days of completed eDiary data required to be evaluable. If <28 days of completed eDiary days were reported, baseline MMDs and similar counting variables were imputed to standardize the count to a 28-day equivalent assuming that the rate of migraine was the same on days with eDiary data and on days with missing data. If any postbaseline 4-week interval had ≥14 but <28 days of completed eDiary data, a similar imputation method was used. If <14 days of eDiary data were available, the observed count for that 4-week interval was set to missing. For weekly migraine data, baseline was defined as baseline MMDs over 4 weeks divided by 4 to compute the 1-week average. After treatment initiation, WMDs were calculated for consecutive 7-day periods. Weeks with 4–7 completed eDiary days were prorated to 7-day equivalent figures; otherwise, weeks were considered missing. The proportion of participants with a migraine day was calculated relative to the number of participants in the mITT population with available eDiary record on the day of consideration.
The daily proportion of participants experiencing a migraine day was analyzed using a generalized linear mixed model (GLMM) assuming a binary distribution for the response and a logit link function. The ADVANCE statistical model included treatment group, visit, prior exposure to a preventive migraine treatment with proven efficacy (yes/no), and treatment group by visit interaction as categorical fixed effects. The ELEVATE statistical model included treatment group, visit, region, number of classes of failed prior preventive treatments (2 and >2), and treatment group by visit interaction as categorical fixed effects. The PROGRESS statistical model included treatment group, visit, stratification of region, stratification of acute medication overuse, stratification of migraine preventive treatment use and number of failures, and treatment group-by-visit interaction as categorical fixed effects. The models also included baseline MMDs and baseline-by-visit interaction as covariates. The unstructured covariance matrix was used to account for the correlation among repeated measurements. The treatment difference in odds ratio (OR) between atogepant and placebo was estimated and tested from this model. All statistical tests reported in the efficacy analyses were conducted 2-sided at α = 0.05 without adjusting for multiplicity.
The atogepant and placebo comparisons for continuous endpoints were analyzed using a mixed model for repeated measures (MMRM) of the change from baseline. The analysis model included the terms as previously described in the GLMM model above. An unstructured covariance matrix was used to model the covariance of within-participants repeated measures. For repeated measures using MMRM, the model parameters were estimated using restricted maximum likelihood estimation incorporating all observed data and assuming data are missing at random. The MMRM model was used to make pairwise comparisons of atogepant to placebo. Each treatment effect and treatment comparison was estimated by the least squares (LS) means and LS mean differences (LSMD), along with standard error and 95% CIs, and the p-value corresponding to the between-treatment group difference.
For the change from baseline in the AIM-D domain scores, baseline scores were calculated using the average daily scores from the last 7 days in the screening/baseline period only if there were ≥4 nonmissing daily scores in the corresponding period. Postbaseline weekly scores were calculated using the average daily scores only if there were ≥4 nonmissing daily scores in the corresponding period. The corresponding weekly scores were calculated by summing the nonmissing daily domain scores and dividing by the number of nonmissing daily domain scores, provided ≥4 daily scores are available; otherwise, it was set to missing. The change from baseline in EQ-5D-5L scores was calculated as the average of available scores in a period if ≥ 50% of daily scores are available; otherwise, the scores were set to missing. The atogepant and placebo comparison for the continuous functional measures were analyzed using MMRM models of the change from baseline. Functional measures with binary variables with multiple postbaseline assessments were analyzed using a GLMM for repeated measures. The analysis model included the model terms as previously described in the MMRM model above. In ELEVATE, if the GLMM model did not converge, functional measures with binary variables were analyzed using a logistic regression model with terms for treatment, region, and number of classes of failed prior preventive treatments (2 and >2) as fixed factors, and baseline MMDs as a covariate. p values are from the test between atogepant and placebo and are reported as nominal p-values, without adjusting for multiplicity. Statistical analyses were performed using SAS software, version 9.4 or newer (SAS Institute, Cary, NC).
Standard Protocol Approvals, Registration, and Patient Consents
All participating sites at all trials obtained approval from a local or central Institutional Review Board and were conducted in accordance with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. All participants provided written informed consent before screening. These studies are registered with ClinicalTrials.gov (NCT03777059, NCT04740827, and NCT03855137). The study protocols and statistical analysis plans have been published.29-31
Data Availability
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan, and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: vivli.org/ourmember/abbvie/ then select “Home”.
Results
Participants and Baseline Demographics
In the ADVANCE, ELEVATE, and PROGRESS trials, 910, 315, and 778 participants were randomized to a treatment arm, respectively. Of the 2 arms included in this analysis, the safety populations included ADVANCE, atogepant 60 mg QD, n = 231; placebo, n = 222; ELEVATE, atogepant 60 mg QD, n = 156; placebo, n = 157; and PROGRESS, atogepant 60 mg QD, n = 261; placebo, n = 255. The mITT populations included ADVANCE, atogepant 60 mg QD, n = 222; placebo, n = 214; ELEVATE, atogepant 60 mg QD, n = 151; placebo, n = 154; and PROGRESS, atogepant 60 mg QD, n = 256; placebo, n = 246 (Figure 1). For each trial, demographics were similar across treatment arms. The majority of participants across the ADVANCE, ELEVATE, and PROGRESS trials were female (87.6% [397/453], 89.5% [280/313], 87.2% [450/516]) and White (85.2% [386/453], 95.8% [300/313], 59.7% [308/516]), with a mean age of 41.6, 42.2, and 42.1 years and a mean body mass index of 30.6, 25.9, and 25.5 kg/m2, respectively (Table 1). Prior oral migraine preventive treatment use occurred in 70% of participants in ADVANCE.29 In PROGRESS, 66% of participants met criteria for acute medication overuse at baseline.30
Figure 1A from New England Journal of Medicine, Jessica Ailani, Richard B. Lipton, Peter J Goadsby, et al. Atogepant for the Preventive Treatment of Migraine, Volume No. 385, Page No. 695–706, Copyright © 2021 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.29 Figure 1B reprinted from Lancet Neurology, 23(4), Tassorelli C, Nagy K, Pozo-Rosich P, et al., “Atogepant for the preventive treatment of episodic migraine in adults with prior inadequate responses to conventional oral preventive treatment (ELEVATE): a randomised, double-blind, placebo-controlled, parallel-group phase 3b trial,” 382–392, Copyright (2024)31; with permission from Elsevier. Figure 1C used with permission from Elsevier Science & Technology Journals, from Pozo-Rosich P et al., Lancet; 2023; 402:775-785. doi:10.1016/S0140-6736(23)01049-830; permission conveyed through Copyright Clearance Center, Inc.
Efficacy Outcomes
The baseline daily rate of participants with a migraine day over the 4-week baseline period across treatment arms ranged from 26.8% to 27.7% in ADVANCE, 32.3% to 33.1% in ELEVATE, and 67.7% to 68.4% in PROGRESS. Atogepant-treated participants had greater reductions in the proportion of participants with a migraine day on day 1 compared with placebo. The OR compared with placebo was 0.39 (95% CI 0.23–0.67; p = 0.0006) in ADVANCE, 0.53 (95% CI 0.29–0.94, p = 0.031) in ELEVATE, and 0.63 (95% CI 0.43–0.93, p = 0.021) in PROGRESS (Figure 2).
The results from ADVANCE have been previously published and are included for reference.26 n = number of participants with a migraine day on day 1 post dose; N = number of participants assessed at timepoint.
Week 1 baseline mean WMDs across treatment arms ranged from 1.88 to 1.93 in ADVANCE, 2.27 to 2.33 in ELEVATE, and 4.74 to 4.80 in PROGRESS. Atogepant-treated participants had greater reductions in mean WMDs starting at week 1 compared with placebo. The LSMD from placebo was −0.74 (95% CI −0.96 to −0.51; p < 0.0001) in ADVANCE, −1.07 (95% CI −1.37 to −0.76, p < 0.0001) in ELEVATE, and −0.85 (95% CI −1.17 to −0.53, p < 0.0001) in PROGRESS. Reductions were consistent through weeks 2, 3, and 4, with comparisons at all timepoints showing greater reductions compared with placebo (Figure 3).
The results from ADVANCE have been previously published and are included for reference.26 n = number of participants assessed at timepoint; N = number of participants randomized to study treatment.
The baseline mean MMDs across treatment arms ranged from 7.50 to 7.74 in ADVANCE, 9.08 to 9.27 in ELEVATE, and 18.95 to 19.17 in PROGRESS. Atogepant-treated participants had greater reductions in mean MMDs in the first 4 weeks of treatment compared with placebo. The LSMD from placebo was −2.35 (95% CI −2.99 to −1.70; p < 0.0001) in ADVANCE, −3.07 (95% CI −3.95 to −2.20, p < 0.0001) in ELEVATE, and −2.43 (95% CI −3.49 to −1.36, p < 0.0001) in PROGRESS (Figure 4).
The results from ADVANCE have been previously published and are included for reference.26 n = number of participants assessed at timepoint; N = number of participants randomized to study treatment.
Functional Outcomes
Baseline mean PDA domain scores of AIM-D across treatment arms ranged from 14.84 to 15.70 in ADVANCE, 16.71 to 18.30 in ELEVATE, and 28.91 to 30.54 in PROGRESS. Atogepant-treated participants had greater reductions (improvements in the performance of daily activities) in mean weekly PDA domain scores starting at week 1 compared with placebo. The LSMD from placebo at week 1 was −4.22 (95% CI −6.22 to −2.23; nominal p < 0.0001) in ADVANCE, −6.76 (95% CI −9.35 to −4.16, nominal p < 0.0001) in ELEVATE, and −5.83 (95% CI −8.36 to −3.30, nominal p < 0.0001) in PROGRESS (Figure 5). Reductions were consistent through weeks 2, 3, and 4, with comparisons at all timepoints showing greater reductions than placebo. A greater proportion of participants achieved the clinically meaningful threshold of ≥9 (for participants with EM) or ≥13.1 (for participants with CM) point improvement from baseline in the PDA domain score at weeks 1, 2, 3, and 4 compared with placebo across all 3 trials (eFigure 2).
n = number of participants assessed at timepoint; N = number of participants randomized to study treatment.
Baseline mean PI domain scores of AIM-D across treatment arms ranged from 11.27 to 11.91 in ADVANCE, 14.10 to 15.61 in ELEVATE, and 25.09 to 27.00 in PROGRESS. Atogepant-treated participants had greater reductions in mean weekly PI domain scores starting at week 1 compared with placebo. The LSMD from placebo at week 1 was −3.03 (95% CI −4.65 to −1.40; nominal p = 0.0003) in ADVANCE, −6.41 (95% CI −8.78 to −4.05, nominal p < 0.0001) in ELEVATE, and −4.12 (95% CI −6.39 to −1.86, nominal p = 0.0004) in PROGRESS (Figure 6). Reductions were consistent through weeks 2, 3, and 4, with comparisons at all timepoints showing greater reductions compared with placebo. A greater proportion of participants achieved the clinically meaningful threshold of ≥6 (for participants with EM) or ≥10 (for participants with CM) point improvement from baseline in the PI domain score at weeks 1, 2, 3, and 4 compared with placebo across all 3 trials (eFigure 3).
n = number of participants assessed at timepoint; N = number of participants randomized to study treatment.
Baseline mean EQ-5D-5L Descriptive System Index scores across treatment arms ranged from 0.85 to 0.87 in ELEVATE and 0.76 to 0.77 in PROGRESS and baseline mean EQ-5D-5L VAS scores ranged from 76.20 to 76.59 in ELEVATE and 64.38 to 65.01 in PROGRESS. Atogepant-treated participants had greater improvements in Descriptive System Index scores and VAS scores compared with placebo. The LSMD from placebo in Descriptive System Index scores at weeks 1–2 was 0.05 (95% CI 0.02–0.07; nominal p < 0.0001) in ELEVATE and 0.04 (95% CI 0.02–0.06; nominal p = 0.0003) in PROGRESS (eFigure 4). The LSMD from placebo in VAS scores at weeks 1–2 was 5.67 (95% CI 2.79–8.56; nominal p = 0.0001) in ELEVATE and 4.47 (95% CI 1.68–7.26; nominal p = 0.0018) in PROGRESS (eFigure 5). Improvements were consistent at week 4, with comparisons showing greater improvements compared with placebo.
Adverse Events
Atogepant 60 mg QD was safe and well tolerated over the 12-week treatment period across the 3 trials.29-31 During the first 4 weeks, TEAEs were reported by 36.4% [84/231], 33.3% [52/156], and 41.0% [107/261] of participants in the atogepant group, compared with 33.3% [74/222], 29.9% [47/157], and 29.4% [75/255] of participants in the placebo group in the ADVANCE, ELEVATE, and PROGRESS trials, respectively (Table 1).
| ADVANCE EM | ELEVATE EM + prior treatment failure to oral preventives | PROGRESS CM | ||||
|---|---|---|---|---|---|---|
| Placebo (n = 222) | Atogepant 60 mg QD (n = 231) | Placebo (n = 157) | Atogepant 60 mg QD (n = 156) | Placebo (n = 255) | Atogepant 60 mg QD (n = 261) | |
| Age, y, mean (SD) | 40.3 (12.8) | 42.5 (12.4) | 43.4 (10.3) | 40.9 (10.7) | 42.0 (12.4) | 41.7 (12.3) |
| Sex, female, n (%) | 198 (89.2) | 199 (86.1) | 141 (89.8) | 139 (89.1) | 225 (88.2) | 225 (86.2) |
| Race, n (%) | ||||||
| White | 194 (87.4) | 192 (83.1) | 151 (96.2) | 149 (95.5) | 151 (59.2) | 157 (60.2) |
| Black or African American | 24 (10.8) | 28 (12.1) | 4 (2.5) | 3 (1.9) | 7 (2.7) | 9 (3.4) |
| Asian | 2 (0.9) | 7 (3.0) | 2 (1.3) | 2 (1.3) | 94 (36.9) | 92 (35.2) |
| American Indian or Alaska Native | 0 | 1 (0.4) | 0 | 0 | 1 (0.4) | 1 (0.4) |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 1 (0.4) | 0 |
| Multiplea | 2 (0.9) | 2 (0.9) | 0 | 2 (1.3) | 1 (0.4) | 2 (0.8) |
| Region, n (%) | ||||||
| North America | 222 (100) | 231 (100) | 20 (12.7) | 20 (12.8) | 75 (29.4) | 79 (30.3) |
| Europe | 0 | 0 | 137 (87.3) | 136 (87.2) | 89 (34.9) | 91 (34.9) |
| East Asia | 0 | 0 | 0 | 0 | 91 (35.7) | 91 (34.9) |
| Adverse events, n (%) | ||||||
| TEAEs | 74 (33.3) | 84 (36.4) | 47 (29.9) | 52 (33.3) | 75 (29.4) | 107 (41.0) |
| Treatment-related TEAEs | 14 (6.3) | 39 (16.9) | 11 (7.0) | 24 (15.4) | 29 (11.4) | 41 (15.7) |
| Serious TEAEsb | 1 (0.5) | 0 | 0 | 0 | 0 | 2 (0.8) |
| TEAEs leading to discontinuationc | 6 (2.7) | 6 (2.6) | 1 (0.6) | 1 (0.6) | 10 (3.9) | 5 (1.9) |
| Death | 0 | 0 | 0 | 0 | 0 | 0 |
Abbreviations: CM = chronic migraine; EM = episodic migraine; QD = once daily; TEAE = treatment-emergent adverse event.
a
Participants who reported multiple races or ethnic groups.
b
In ADVANCE, there was 1 participant with ≥1 serious TEAE in the placebo arm (brain injury and negative pressure pulmonary edema), and it was not related to treatment per investigator judgement. In PROGRESS, there were 2 participants with ≥1 serious TEAEs in the atogepant 60 mg QD arm (vaccination complication and spinal cord neoplasm), both not related to treatment per investigator judgment.
c
In ADVANCE, 6 participants on placebo (1 abdominal pain, 1 musculoskeletal chest pain, 1 brain injury, 1 migraine, 1 suicidal ideation, 1 renal colic, and 1 negative pressure pulmonary edema) and 6 participants on atogepant 60 mg QD (1 ear pain, 1 constipation, 1 nausea, 1 fatigue, 1 decreased appetite, 1 diabetes mellitus, 1 agitation, 1 insomnia, 1 hyperhidrosis, 1 pruritus generalized, and 1 rash) had ≥1 TEAE leading to treatment discontinuation. In ELEVATE, 1 participant on placebo (migraine) and 1 participant on atogepant 60 mg QD (nausea) had ≥1 TEAE leading to treatment discontinuation. In PROGRESS, 10 participants on placebo (2 nausea, 2 abdominal pain, 2 constipation, 1 diarrhea, 1 dyspepsia, 1 dizziness, 4 migraine, 1 disturbance in attention, and 1 headache) and 5 participants on atogepant 60 mg QD (2 nausea, 1 malaise, 1 spinal cord neoplasm, 1 dizziness, and 1 migraine) had ≥1 TEAE leading to treatment discontinuation.
Discussion
A rapid onset of efficacy for migraine preventive treatments is a clinically desirable and meaningful treatment attribute prioritized by people living with migraine and by clinicians.8,9,14,37 This analysis reports the efficacy and improvements in functional measures during the first 4 weeks of treatment with atogepant 60 mg QD using data from 3 pivotal trials, ADVANCE, ELEVATE, and PROGRESS. The proportion of participants with a migraine day on day 1 was reduced with atogepant treatment. Atogepant also demonstrated a reduction in WMDs as early as week 1 and in MMDs across the first 4 weeks of treatment. Improvements in functional measures were shown with atogepant as early as week 1 for both domains of the AIM-D and at weeks 1–2 for both components of the EQ-5D-5L. These results were observed across all 3 studies, illustrating a consistent effect across a representative spectrum of migraine disease severity. The reduction in MMDs and the improvement in AIM-D during the first 4 weeks are consistent with the significant reduction in MMDs and improvement in AIM-D during the 12-week treatment period previously reported for all 3 trials (eTable 1). The atogepant safety profile during the first 4 weeks is consistent with the safety profile during the previously reported 12-week treatment periods (eTable 2).29-31
The onset of efficacy of preventive treatments, including onabotulinumtoxinA and injectable mAb treatments targeting CGRP or the CGRP receptor, has been studied in multiple secondary and post hoc analyses.16 Participants treated with onabotulinumtoxinA for CM saw a reduction in headache and migraine days per week at week 1.17 Galcanezumab (CGRP-targeted mAb) treated participants with EM demonstrated reduced MHDs at week 1 and a lower proportion had migraine headaches beginning 1 day postinjection.18,19 Erenumab (mAb targeting the canonical CGRP receptor) treated participants with EM and CM showed reductions in WMDs within the first week of treatment.20 Eptinezumab (CGRP-targeted mAb) treatment was associated with a reduction in the proportion of participants with EM and CM with a migraine at day 1 postinjection.21,22 Fremanezumab (CGRP-targeted mAb) treatment was associated with reduced mean weekly headache days at week 1 and increased proportions of participants with EM and CM reporting no headache 1 day postinjection.23,24 The efficacy results presented here show that the rapid onset of treatment effects seen with injectable CGRP targeted treatments or onabotulinumtoxinA can also be achieved with once daily oral atogepant.
In addition to reducing migraine days, the CGRP mAbs have shown improvements in various functional measures at week 4.22,24,38-43 In this analysis, atogepant-treated participants showed improvements in the PDA and PI domain scores of AIM-D over the first week of treatment. The proportion of participants achieving clinically relevant improvements in the PDA and PI domains increased over 4 weeks. Atogepant-treated participants also demonstrated improvements in the EQ-5D-5L Descriptive System Index and VAS scores starting at weeks 1–2. Daily administration of EQ-5D-5L represents a methodological change from earlier studies. Traditionally, EQ-5D-5L is administered on a single day, which may or may not be a headache day, introducing a high level of measurement error based on temporal sampling. Daily administration allowed us to sample quality-of-life effects on both headache and headache-free days. Previous preventive treatments have demonstrated functional improvements starting at week 4; however, the results presented here of treatment with oral atogepant are the first to demonstrate improvements in the participants' ability to complete daily activities without limitations and in self-assessed health status as early as week 1. These early improvements (i.e., reduction) of the activity impairment associated with migraine as early as week 1 have the potential to affect individuals' day-to-day lives by restoring function, the ability to perform daily activities, and work productivity.
Current conventional, oral preventive treatment classes usually require dose titration based on therapeutic effects and side effects, and the assessment of therapeutic effects may take weeks or months.10,11 Patients cite a perceived lack of efficacy as one of the largest reasons for discontinuing treatment, in addition to side effects.44 When patients with EM or CM were asked to value early efficacy outcomes, a reduction in the likelihood of a migraine on day 1 postdose and a clinically relevant reduction in migraine days during the first month postdose were similarly valued.45 Reported here, atogepant treatment demonstrated greater reductions in the proportion of participants with a migraine day at day 1 and greater reductions in mean MMDs during the first 4 weeks of treatment. These results from 3 atogepant trials consistently show improvements in early timepoints reported to be of clinical value to individuals with migraine.
The study populations of all 3 trials consisted of mostly female and mostly White participants, so results may not be generalizable to the full patient population. In addition, the trials excluded participants if they used opioids or barbiturates ≥4 days (≥2 days for ADVANCE) per month in the 3 months before visit 1 or during the baseline period, and those who did not have a response to >4 preventive treatments (>4 classes of preventive treatments in ELEVATE). Studies including these populations are needed. These are group-level analyses limited to the first 4 weeks of treatment and should not be interpreted as predictive of subsequent responses. Group-level analyses should not be used to infer individual responses because variations may be observed within individuals.
In summary, atogepant demonstrated greater reductions in the proportion of participants with a migraine day on day 1, WMDs as early as week 1, and MMDs in the first 4 weeks of treatment compared with placebo. Improvements in efficacy outcomes were accompanied by the first demonstration of a preventive treatment to improve PROs assessing functional and quality-of-life outcomes as early as week 1. These results were consistent across three phase 3 trials in populations of participants with EM, EM with prior inadequate response to conventional, oral preventive treatments, and CM. The analyses reported here demonstrate the early efficacy and functional improvements of atogepant and address a key unmet need of providing preventive treatment options with early benefits across the spectrum of migraine disease state severity.
Glossary
- AE
- adverse event
- AIM-D
- Activity Impairment in Migraine-Diary
- CGRP
- calcitonin gene–related peptide
- CM
- chronic migraine
- EM
- episodic migraine
- EQ-5D-5L
- European Quality-of-Life 5-Dimension 5-Level
- GLMM
- generalized linear mixed model
- LS
- least squares
- LSMD
- LS mean differences
- mAb
- monoclonal antibody
- mITT
- modified intent-to-treat
- MMD
- monthly migraine day
- MMRM
- mixed model for repeated measures
- MWPC
- meaningful within-patient change
- OR
- odds ratio
- PDA
- performance of daily activities
- PI
- physical impairment
- TEAE
- treatment-emergent AE
- WMD
- weekly migraine day
Acknowledgment
Editorial assistance was provided to the authors by Angela T. Hadsell, BA, of AbbVie (North Chicago, IL, USA) and was funded by AbbVie. AbbVie and the authors thank all the trial investigators and the patients who participated in these clinical trials.
Supplementary Materials
eFigure_1
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eFigure_2
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eFigure_3
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eFigure_4
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eFigure_5
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- 146.67 KB
eMethods
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- 114.12 KB
eTable_1
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- 104.58 KB
eTable_2
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- 79.95 KB
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Information & Authors
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Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Publication History
Received: February 6, 2024
Accepted: November 1, 2024
Published online: December 23, 2024
Published in print: January 28, 2025
Disclosure
R.B. Lipton has received research support from the NIH, the FDA, and the National Headache Foundation; serves as a consultant for, advisory board member of, or has received honoraria or research support from AbbVie/Allergan, Amgen, Biohaven, Dr. Reddy's Laboratories (Promius), electroCore, Eli Lilly, GlaxoSmithKline, Lundbeck, Merck, Novartis, Teva, Vector, and Vedanta Research; receives royalties from Wolff's Headache, 8th edition (Oxford University Press, 2009), and Informa; and holds stock/options in Axon, Biohaven, CoolTech, and Manistee. C. Tassorelli has participated in advisory boards for AbbVie, Dompé, Eli Lilly, Ipsen, Lundbeck, Medscape, Pfizer, and Teva; has lectured at symposia sponsored by AbbVie, Eli Lilly, Lundbeck, Pfizer, and Teva; is principal investigator or collaborator in clinical trials sponsored by AbbVie, Eli Lilly, Ipsen, Lundbeck, Pfizer, and Teva; and has received research grants from the European Commission, the Italian Ministry of Health, the Italian Ministry of University, the Migraine Research Foundation, and the Italian Multiple Sclerosis Foundation. U. Reuter has served on advisory boards for Amgen, Allergan, AbbVie, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva; has received institutional honoraria for lectures from Amgen, Allergan, AbbVie, Eli Lilly, Lundbeck, Novartis, electroCore, Medscape, StreaMedUp, Springer, and Teva; received institutional honoraria for consulting services from Lundbeck, Pfizer, and AbbVie; received research funding from Novartis (CHERUB01) and the German Federal Ministry of Education and Research; and is an associate editor of the Journal of Headache and Pain. A. Harriott has received personal compensation for serving as an officer or member of the Board of Directors for Headache Cooperative of New England. The institution of Dr. Harriott has received research support from electroCore. She has a non-compensated relationship as an author with AbbVie that is relevant to AAN interests or activities. D. Holle-Lee received honoraria for consulting from AbbVie/Allergan, Amgen, Eli Lilly, Novartis, Teva, Lundbeck, Hormosan, and Zuellig Pharma. C.H. Gottschalk has been a paid consultant for Alder/Lundbeck, Biohaven, Amgen/Novartis, Theranica, Axsome, Upsher Smith, Spherix Global Insights, and Vorso; has been a past member of speaker bureaus for Amgen/Novartis, Allergan/AbbVie, Biohaven, Lilly, Theranica, and Upsher Smith; served as an associate editor of Headache until 2020; and is a board member of the Headache Cooperative of New England (HCNE). P. Gandhi, B. Neel, Y. Liu, H. Guo, J. Stokes, K. Nagy, B. Dabruzzo, and J.H. Smith are all employees of AbbVie Inc. and may hold AbbVie stock. Go to Neurology.org/N for full disclosures.
Study Funding
AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Authors
Author Contributions
R.B. Lipton: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. P. Gandhi: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. C. Tassorelli: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. U. Reuter: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. A.M. Harriott: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. D. Holle: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. C.H. Gottschalk: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. B. Neel: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. Y. Liu: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. H. Guo: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. J. Stokes: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. K. Nagy: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. B. Dabruzzo: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. J.H. Smith: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data.
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